Associations between brain microstructures, metabolites, and cognitive deficits during chronic HIV-1 infection of humanized mice

Molecular Neurodegeneration

Santhi Gorantla³  Howard E Gendelman⁴  Larisa Y Poluektova³  Harris A Gelbard¹  Stephen Bonasera⁴  Edward Makarov³  Robin High⁵  Natasha Fields³  Sidra P Akhter³  Adrian A Epstein³  Jaclyn Knibbe³  Prasanta K Dash³  Michael D Boska² 

[1] Department of Neurology, Center for Neural Development and Disease, University of Rochester Medical Center, Rochester, NY 14642, USA;Department of Radiology, University of Nebraska Medical Center, Omaha, NE 68198, USA;Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA;Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA;College of Public Health, University of Nebraska Medical Center, Omaha, NE 68198, USA

关键词: Humanized mice;    HIV-1;    Diffusion tensor imaging;    Behavioral and cognitive deficits;    ¹H magnetic resonance spectroscopy;   

Others  :  1138620
DOI  :  10.1186/1750-1326-9-58

 received in 2014-08-26, accepted in 2014-12-07,  发布年份 2014

【 摘 要 】

Background

Host-species specificity of the human immunodeficiency virus (HIV) limits pathobiologic, diagnostic and therapeutic research investigations to humans and non-human primates. The emergence of humanized mice as a model for viral infection of the nervous system has overcome such restrictions enabling research for HIV-associated end organ disease including behavioral, cognitive and neuropathologic deficits reflective of neuroAIDS. Chronic HIV-1 infection of NOD/scid-IL-2Rg_c^null mice transplanted with human CD34⁺ hematopoietic stem cells (CD34-NSG) leads to persistent viremia, profound CD4⁺ T lymphocyte loss and infection of human monocyte-macrophages in the meninges and perivascular spaces. Murine cells are not infected with virus.

Methods

Changes in mouse behavior were measured, starting at 8 weeks after viral infection. These were recorded coordinate with magnetic resonance spectroscopy metabolites including N-acetylaspartate (NAA), creatine and choline. Diffusion tensor magnetic resonance imaging (DTI) was recorded against multispectral immunohistochemical staining for neuronal markers that included microtubule associated protein-2 (MAP2), neurofilament (NF) and synaptophysin (SYN); for astrocyte glial fibrillary acidic protein (GFAP); and for microglial ionized calcium binding adaptor molecule 1 (Iba-1). Oligodendrocyte numbers and integrity were measured for myelin associated glycoprotein (MAG) and myelin oligodendrocyte glycoprotein (MOG) antigens.

Results

Behavioral abnormalities were readily observed in HIV-1 infected mice. Longitudinal open field activity tests demonstrated lack of habituation indicating potential for memory loss and persistent anxiety in HIV-1 infected mice compared to uninfected controls. End-point NAA and creatine in the cerebral cortex increased with decreased MAG. NAA and glutamate decreased with decreased SYN and MAG. Robust inflammation reflected GFAP and Iba-1 staining intensities. DTI metrics were coordinate with deregulation of NF, Iba-1, MOG and MAG levels in the whisker barrel and MAP2, NF, MAG, MOG and SYN in the corpus callosum.

Conclusions

The findings are consistent with some of the clinical, biochemical and pathobiologic features of human HIV-1 nervous system infections. This model will prove useful towards investigating the mechanisms of HIV-1 induced neuropathology and in developing novel biomarkers and therapeutic strategies for disease.

【 授权许可】

   
2014 Boska et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

Figure 8.

Figure 9.

Figure 10.

【 参考文献 】

• [1]Kraft-Terry SD, Stothert AR, Buch S, Gendelman HE: HIV-1 neuroimmunity in the era of antiretroviral therapy. Neurobiol Dis 2010, 37:542-548.
• [2]Robertson K, Liner J, Heaton R: Neuropsychological assessment of HIV-infected populations in international settings. Neuropsychol Rev 2009, 19:232-249.
• [3]Heaton RK, Franklin DR, Ellis RJ, McCutchan JA, Letendre SL, Leblanc S, Corkran SH, Duarte NA, Clifford DB, Woods SP, Collier AC, Marra CM, Morgello S, Mindt MR, Taylor MJ, Marcotte TD, Atkinson JH, Wolfson T, Gelman BB, McArthur JC, Simpson DM, Abramson I, Gamst A, Fennema-Notestine C, Jernigan TL, Wong J, Grant I, CHARTER Group: HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors. J Neurovirol 2011, 17:3-16.
• [4]Pozniak A, Rackstraw S, Deayton J, Barber T, Taylor S, Manji H, Melvin D, Croston M, Nightingale S, Kulasegaram R, Pitkanen M, Winston A: HIV-associated neurocognitive disease: case studies and suggestions for diagnosis and management in different patient sub-groups. Antivir Ther 2014, 19(1):1-13.
• [5]Gorantla S, Poluektova L, Gendelman HE: Rodent models for HIV-associated neurocognitive disorders. Trends Neurosci 2012, 35:197-208.
• [6]Jaeger LB, Nath A: Modeling HIV-associated neurocognitive disorders in mice: new approaches in the changing face of HIV neuropathogenesis. Dis Model Mech 2012, 5:313-322.
• [7]Koppensteiner H, Brack-Werner R, Schindler M: Macrophages and their relevance in Human Immunodeficiency Virus Type I infection. Retrovirology 2012, 9:82. BioMed Central Full Text
• [8]Palmer S, Josefsson L, Coffin JM: HIV reservoirs and the possibility of a cure for HIV infection. J Intern Med 2011, 270:550-560.
• [9]Gelbard HA, Gendelman HE: Lipids and cognition make good bedfellows for neuroAIDS. Neurology 2013, 81(17):1480-1481.
• [10]Gannon P, Khan MZ, Kolson DL: Current understanding of HIV-associated neurocognitive disorders pathogenesis. Curr Opin Neurol 2011, 24:275-283.
• [11]del Palacio M, Alvarez S, Munoz-Fernandez MA: HIV-1 infection and neurocognitive impairment in the current era. Rev Med Virol 2012, 22:33-45.
• [12]Yilmaz A, Price RW, Gisslen M: Antiretroviral drug treatment of CNS HIV-1 infection. J Antimicrob Chemother 2012, 67:299-311.
• [13]Kahouadji Y, Dumurgier J, Sellier P, Lapalus P, Delcey V, Bergmann J, Hugon J, Paquet C: Cognitive function after several years of antiretroviral therapy with stable central nervous system penetration score. HIV Med 2013, 14:311-315.
• [14]McCombe JA, Vivithanaporn P, Gill MJ, Power C: Predictors of symptomatic HIV-associated neurocognitive disorders in universal health care. HIV Med 2013, 14:99-107.
• [15]Smurzynski M, Wu K, Letendre S, Robertson K, Bosch RJ, Clifford DB, Evans S, Collier AC, Taylor M, Ellis R: Effects of central nervous system antiretroviral penetration on cognitive functioning in the ALLRT cohort. Aids 2011, 25:357-365.
• [16]Airoldi M, Bandera A, Trabattoni D, Tagliabue B, Arosio B, Soria A, Rainone V, Lapadula G, Annoni G, Clerici M, Gori A: Neurocognitive impairment in HIV-infected naive patients with advanced disease: the role of virus and intrathecal immune activation. Clin Dev Immunol 2012, 2012:467154.
• [17]Alfahad TB, Nath A: Update on HIV-associated neurocognitive disorders. Curr Neurol Neurosci Rep 2013, 13:387.
• [18]Clark US, Cohen RA: Brain dysfunction in the era of combination antiretroviral therapy: implications for the treatment of the aging population of HIV-infected individuals. Curr Opin Investig Drugs 2010, 11:884-900.
• [19]Spudich SS, Ances BM: Neurologic complications of HIV infection: highlights from the 2013 conference on retroviruses and opportunistic infections. Topics in antiviral Med 2013, 21:100-108.
• [20]Gorantla S, Makarov E, Finke-Dwyer J, Gebhart CL, Domm W, Dewhurst S, Gendelman HE, Poluektova LY: CD8+ cell depletion accelerates HIV-1 immunopathology in humanized mice. J Immunol 2010, 184:7082-7091.
• [21]Gorantla S, Makarov E, Finke-Dwyer J, Castanedo A, Holguin A, Gebhart CL, Gendelman HE, Poluektova L: Links between progressive HIV-1 infection of humanized mice and viral neuropathogenesis. Am J Pathol 2010, 177:2938-2949.
• [22]Dash PK, Gorantla S, Gendelman HE, Knibbe J, Casale GP, Makarov E, Epstein AA, Gelbard HA, Boska MD, Poluektova LY: Loss of neuronal integrity during progressive HIV-1 infection of humanized mice. J Neurosci 2011, 31:3148-3157.
• [23]Dash PK, Gendelman HE, Roy U, Balkundi S, Alnouti Y, Mosley RL, Gelbard HA, McMillan J, Gorantla S, Poluektova LY: Long-acting nanoformulated antiretroviral therapy elicits potent antiretroviral and neuroprotective responses in HIV-1-infected humanized mice. Aids 2012, 26:2135-2144.
• [24]Sun B, Abadjian L, Rempel H, Calosing C, Rothlind J, Pulliam L: Peripheral biomarkers do not correlate with cognitive impairment in highly active antiretroviral therapy-treated subjects with human immunodeficiency virus type 1 infection. J Neurovirol 2010, 16:115-124.
• [25]Norman LR, Basso M, Kumar A, Malow R: Neuropsychological consequences of HIV and substance abuse: a literature review and implications for treatment and future research. Curr Drug Abuse Rev 2009, 2:143-156.
• [26]Stanford SC: The open field test: reinventing the wheel. J Psychopharmacol 2007, 21:134-135.
• [27]Bolivar VJ, Caldarone BJ, Reilly AA, Flaherty L: Habituation of activity in an open field: a survey of inbred strains and F1 hybrids. Behav Genet 2000, 30:285-293.
• [28]Prut L, Belzung C: The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur J Pharmacol 2003, 463:3-33.
• [29]Willi R, Winter C, Wieske F, Kempf A, Yee BK, Schwab ME, Singer P: Loss of EphA4 impairs short-term spatial recognition memory performance and locomotor habituation. Genes Brain Behav 2012, 11(8):1020-1031.
• [30]Lamprea MR, Cardenas FP, Setem J, Morato S: Thigmotactic responses in an open-field. Braz J Med Biol Res 2008, 41:135-140.
• [31]Fox HS, Gendelman HE: Commentary: animal models of neuroAIDS. J Neuroimmune Pharmacol 2012, 7:301-305.
• [32]Weed MR, Steward DJ: Neuropsychopathology in the SIV/macaque model of AIDS. Front Biosci 2005, 10:710-727.
• [33]Gold LH, Fox HS, Henriksen SJ, Buchmeier MJ, Weed MR, Taffe MA, Huitron-Resendiz S, Horn TF, Bloom FE: Longitudinal analysis of behavioral, neurophysiological, viral and immunological effects of SIV infection in rhesus monkeys. J Med Primatol 1998, 27:104-112.
• [34]Gorantla S, Sneller H, Walters L, Sharp JG, Pirruccello SJ, West JT, Wood C, Dewhurst S, Gendelman HE, Poluektova L: Human immunodeficiency virus type 1 pathobiology studied in humanized BALB/c-Rag2-/-gammac-/- mice. J Virol 2007, 81:2700-2712.
• [35]Epstein AA, Narayanasamy P, Dash PK, High R, Bathena SP, Gorantla S, Poluektova LY, Alnouti Y, Gendelman HE, Boska MD: Combinatorial assessments of brain tissue metabolomics and histopathology in rodent models of human immunodeficiency virus infection. J Neuroimmune Pharmacol 2013, 8(5):1224-1238.
• [36]Koopmans PP, Ellis R, Best BM, Letendre S: Should antiretroviral therapy for HIV infection be tailored for intracerebral penetration? Neth J Med 2009, 67:206-211.
• [37]Kranick SM, Nath A: Neurologic complications of HIV-1 infection and its treatment in the era of antiretroviral therapy. Continuum 2012, 18:1319-1337.
• [38]Price RW, Swanstrom R: Targeting chronic central nervous system HIV infection. Antivir Ther 2012, 17:1227-1231.
• [39]Amaral AI, Meisingset TW, Kotter MR, Sonnewald U: Metabolic aspects of neuron-oligodendrocyte-astrocyte interactions. Front Endocrinol 2013, 4:54.
• [40]Madhavarao CN, Chinopoulos C, Chandrasekaran K, Namboodiri MA: Characterization of the N-acetylaspartate biosynthetic enzyme from rat brain. J Neurochem 2003, 86:824-835.
• [41]Chakraborty G, Mekala P, Yahya D, Wu G, Ledeen RW: Intraneuronal N-acetylaspartate supplies acetyl groups for myelin lipid synthesis: evidence for myelin-associated aspartoacylase. J Neurochem 2001, 78:736-745.
• [42]Dousset V, Armand JP, Lacoste D, Mieze S, Letenneur L, Dartigues JF, Caill JM: Magnetization transfer study of HIV encephalitis and progressive multifocal leukoencephalopathy. Groupe d’Epidemiologie Clinique du SIDA en Aquitaine. AJNR Am J Neuroradiol 1997, 18:895-901.
• [43]Ratai EM, Pilkenton SJ, Greco JB, Lentz MR, Bombardier JP, Turk KW, He J, Joo CG, Lee V, Westmoreland S, Halpern E, Lackner AA, González RG: In vivo proton magnetic resonance spectroscopy reveals region specific metabolic responses to SIV infection in the macaque brain. BMC Neurosci 2009, 10:63. BioMed Central Full Text
• [44]Chang L, Ernst T, Witt MD, Ames N, Gaiefsky M, Miller E: Relationships among brain metabolites, cognitive function, and viral loads in antiretroviral-naive HIV patients. Neuroimage 2002, 17:1638-1648.
• [45]Tumati S, Martens S, Aleman A: Magnetic resonance spectroscopy in mild cognitive impairment: systematic review and meta-analysis. Neurosci Biobehav Rev 2013, 37:2571-2586.
• [46]Horder J, Lavender T, Mendez MA, O’Gorman R, Daly E, Craig MC, Lythgoe DJ, Barker GJ, Murphy DG: Reduced subcortical glutamate/glutamine in adults with autism spectrum disorders: a [(1)H]MRS study. Transl Psychiatry 2013, 3:e279.
• [47]Barber TJ, Bradshaw D, Hughes D, Leonidou L, Margetts A, Ratcliffe D, Thornton S, Pozniak A, Asboe D, Mandalia S, Boffito M, Davies N, Gazzard B, Catalan J: Screening for HIV-related neurocognitive impairment in clinical practice: challenges and opportunities. AIDS Care 2014, 26(2):160-168.
• [48]Zipursky AR, Gogolishvili D, Rueda S, Brunetta J, Carvalhal A, McCombe JA, Gill MJ, Rachlis A, Rosenes R, Arbess G, Marcotte T, Rourke SB: Evaluation of brief screening tools for neurocognitive impairment in HIV/AIDS: a systematic review of the literature. Aids 2013, 27(15):2385-2401.
• [49]Zink WE, Anderson E, Boyle J, Hock L, Rodriguez-Sierra J, Xiong H, Gendelman HE, Persidsky Y: Impaired spatial cognition and synaptic potentiation in a murine model of human immunodeficiency virus type 1 encephalitis. J Neurosci 2002, 22:2096-2105.
• [50]Avgeropoulos N, Kelley B, Middaugh L, Arrigo S, Persidsky Y, Gendelman HE, Tyor WR: SCID mice with HIV encephalitis develop behavioral abnormalities. J Acquir Immune Defic Syndr Hum Retrovirol 1998, 18:13-20.
• [51]Hahn YK, Podhaizer EM, Farris SP, Miles MF, Hauser KF, Knapp PE: Effects of chronic HIV-1 Tat exposure in the CNS: heightened vulnerability of males versus females to changes in cell numbers, synaptic integrity, and behavior. Brain Struct Funct 2013. in press
• [52]D’Hooge R, Franck F, Mucke L, De Deyn PP: Age-related behavioural deficits in transgenic mice expressing the HIV-1 coat protein gp120. Eur J Neurosci 1999, 11:4398-4402.
• [53]Paris JJ, Singh HD, Ganno ML, Jackson P, McLaughlin JP: Anxiety-like behavior of mice produced by conditional central expression of the HIV-1 regulatory protein, Tat. Psychopharmacology (Berl) 2014, 231:2349-2360.
• [54]Carey AN, Sypek EI, Singh HD, Kaufman MJ, McLaughlin JP: Expression of HIV-Tat protein is associated with learning and memory deficits in the mouse. Behav Brain Res 2012, 229:48-56.
• [55]Avgeropoulos NG, Burris GW, Ohlandt GW, Wesselingh SL, Markham RB, Tyor WR: Potential relationships between the presence of HIV, macrophages, and astrogliosis in SCID mice with HIV encephalitis. J NeuroAIDS 1998, 2:1-20.
• [56]Robertson K, Jiang H, Kumwenda J, Supparatpinyo K, Evans S, Campbell TB, Price R, Tripathy S, Kumarasamy N, La Rosa A, Santos B, Silva MT, Montano S, Kanyama C, Faesen S, Murphy R, Hall C, Marra CM, Marcus C, Berzins B, Allen R, Housseinipour M, Amod F, Sanne I, Hakim J, Walawander A, Nair A, 5199 Study Team: Improved neuropsychological and neurological functioning across three antiretroviral regimens in diverse resource-limited settings: AIDS Clinical Trials Group study a5199, the International Neurological Study. Clin Infect Dis 2012, 55:868-876.
• [57]Al-Khindi T, Zakzanis KK, van Gorp WG: Does antiretroviral therapy improve HIV-associated cognitive impairment? A quantitative review of the literature. J Int Neuropsychol Soc 2011, 17:956-969.
• [58]Crusio WE: Genetic dissection of mouse exploratory behaviour. Behav Brain Res 2001, 125:127-132.
• [59]Jost CR, Van Der Zee CE, In ‘t Zandt HJ, Oerlemans F, Verheij M, Streijger F, Fransen J, Heerschap A, Cools AR, Wieringa B: Creatine kinase B-driven energy transfer in the brain is important for habituation and spatial learning behaviour, mossy fibre field size and determination of seizure susceptibility. Eur J Neurosci 2002, 15:1692-1706.
• [60]Johnson RT, McArthur JC, Narayan O: The neurobiology of human immunodeficiency virus infections. FASEB J 1988, 2:2970-2981.
• [61]Ances BM, Ellis RJ: Dementia and neurocognitive disorders due to HIV-1 infection. Semin Neurol 2007, 27:86-92.
• [62]Anderson E, Zink W, Xiong H, Gendelman HE: HIV-1-associated dementia: a metabolic encephalopathy perpetrated by virus-infected and immune-competent mononuclear phagocytes. J Acquir Immune Defic Syndr 2002, 31(Suppl 2):S43-S54.
• [63]Valcour V, Sithinamsuwan P, Letendre S, Ances B: Pathogenesis of HIV in the central nervous system. Curr HIV/AIDS Rep 2011, 8:54-61.
• [64]Kraft-Terry SD, Buch SJ, Fox HS, Gendelman HE: A coat of many colors: neuroimmune crosstalk in human immunodeficiency virus infection. Neuron 2009, 64:133-145.
• [65]Spudich S, Gonzalez-Scarano F: HIV-1-related central nervous system disease: current issues in pathogenesis, diagnosis, and treatment. Cold Spring Harb Perspect Med 2012, 2:a007120.
• [66]Burdo TH, Lackner A, Williams KC: Monocyte/macrophages and their role in HIV neuropathogenesis. Immunol Rev 2013, 254:102-113.
• [67]Gendelman HE, Orenstein JM, Martin MA, Ferrua C, Mitra R, Phipps T, Wahl LA, Lane HC, Fauci AS, Burke DS, Skillman D, Meltzer MS: Efficient isolation and propagation of human immunodeficiency virus on recombinant colony-stimulating factor 1-treated monocytes. J Exp Med 1988, 167:1428-1441.
• [68]Ratiney H, Coenradie Y, Cavassila S, van Ormondt D, Graveron-Demilly D: Time-domain quantitation of 1H short echo-time signals: background accommodation. MAGMA 2004, 16:284-296.
• [69]Ratiney H, Sdika M, Coenradie Y, Cavassila S, van Ormondt D, Graveron-Demilly D: Time-domain semi-parametric estimation based on a metabolite basis set. NMR Biomed 2005, 18:1-13.
• [70]Boska MD, Hasan KM, Kibuule D, Banerjee R, McIntyre E, Nelson JA, Hahn T, Gendelman HE, Mosley RL: Quantitative diffusion tensor imaging detects dopaminergic neuronal degeneration in a murine model of Parkinson’s disease. Neurobiol Dis 2007, 26:590-596.
• [71]Basser PJ, Mattiello J, LeBihan D: Estimation of the effective self-diffusion tensor from the NMR spin echo. J Magn Reson B 1994, 103:247-254.
• [72]Basser PJ, Mattiello J, LeBihan D: MR diffusion tensor spectroscopy and imaging. Biophys J 1994, 66:259-267.
• [73]Hasan KM, Basser PJ, Parker DL, Alexander AL: Analytical computation of the eigenvalues and eigenvectors in DT-MRI. J Magn Reson 2001, 152:41-47.
• [74]Hasan KM: Diffusion tensor eigenvalues or both mean diffusivity and fractional anisotropy are required in quantitative clinical diffusion tensor MR reports: fractional anisotropy alone is not sufficient. Radiology 2006, 239:611-612. author reply 612-613
• [75]Westfall PH, Manage A: How well do multiple testing methods scale up when both n and k increase? J Biopharm Stat 2011, 21:583-594.